Genome-Guided Therapeutic Vulnerabilities in Esophageal Cancer

项目3摘要

PROJECT 3 ABSTRACT Esophageal cancer is a common and deadly disease with inadequate therapies. Systemic therapy remains reliant upon empiric chemotherapy, given alone in the palliative setting and in conjunction with radiation for adjuvant care. The convergence of our rapidly expanding knowledge of the cancer genome and the development of a myriad of targeted agents has created a new and unique opportunity to advance rational, biomarker-driven therapies for esophageal cancer. Our genomic studies of esophageal cancers have identified two dominant classes of targets: highly recurrent amplifications targeting receptor tyrosine kinases, most frequently EGFR and ERBB2 (Her2), and amplified modulators of the cell cycle, Cyclin D1, Cyclin E1 and CDK6. Despite strong genomic rationale for these targets and the available and emerging inhibitors, we lack pre-clinical data to guide the development strategies to exploit these targets. Therefore, we propose to develop strategies to target esophageal cancers harboring targetable genomic alterations of receptor tyrosine kinases and of cell cycle mediators utilizing genomically-characterized model systems in in vitro and in vivo testing of therapeutic agents. We will tests hypotheses regarding means to target tumors, both with single targeted therapies and with rational combinations. Throughout this proposal, we integrate efforts with the other projects in this Project Grant and make extensive use of core resources through this Project and evaluate targeted strategies that for both esophageal squamous cell carcinoma and esophageal adenocarcinoma. In Aim 1, we propose to evaluate the cell cycle kinase CDK2 as a therapeutic target in esophageal carcinomas by evaluating this target using genetic and pharmacologic tools in esophageal cancer models with genomic lesions that make them more likely dependent upon CDK2, amplifications of genes encoding cyclin D1 and cyclin E1. In Aim 2, we evaluate distinct classes of small molecule and antibody tyrosine kinase inhibitors in esophageal cancer model systems with genomic alterations leading to oncogenic activation of ERBB family kinases EGFR and ERBB2. Furthermore, in Aim 2 we also test the ability to augment effects of ERBB-directed therapy in esophageal cancer models by combinations with inhibitors of either the MAPK or PI3-K pathway. Finally, in Aim 3 we evaluate the phenomena we have observed that esophageal cancers often harbor genomic aberrations impacting both cell cycle mediators and ERBB-family kinases in the same tumor, suggesting that combining inhibitors of these two sets of targets may be efficacious for these tumors. We therefore propose to characterize the patterns of co-occurrence of these targets in the genomes of these cancers and their co-expression in a large panel of tissue samples. Additionally, we will utilize the example of esophageal cancer models with co-amplification of both EGFR and Cyclin D1 to systematically evaluate distinct methods of combing inhibitors to these pathways. Together, these three aims are designed to pursue specific hypotheses that will allow us to much more rapidly develop new more effective therapeutic strategies for patients with these deadly diseases.